Yersinia pestis is the etiologic agent of the bubonic plague. Many historians consider the plague as the most devastating infectious disease in human history. Today, there are less than a dozen cases of the plague in the United States. But, after recent terrorist events, the CDC has identified Y. pestis as a serious biological weapons threat (1). Thus, an understanding of how Y. pestis causes disease will allow us to design appropriate therapies. Yersinia pestis secretes a capsule-like antigen called fraction (F1) 1 and very thin fibrillae known as pH 6 antigen. Both of these structures are assembled via the chaperone-usher system. We are the world's authorities on this pathway, as we have dissected the molecular details of chaperone-subunit interactions and function. The goal of this project will be to solve the crystal structures of F1 antigen (Caf1)-Caf1M complex and the pH 6 antigen (PsaA)-PsaB complex. From these structures, we will elucidate the details of chaperone-subunit interactions as well as predict the structural basis of F1 capsule and pH 6 antigen assembly. Using rational drug design, we will create novel antibacterials that will inhibit chaperone function and/or interfere with capsule/fibrillae assembly. Also, the complexes will be used as vaccines, in a strategy similar to that which we have used with the E. coLI FimC-FimH complex to protect against urinary tract infections. This work has the potential to lead to new vaccines to prevent plague, and new drugs to treat this deadly infection.